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M T Pellecchia,
G Santangelo,
M Picillo,
R Pivonello,
K Longo,
C Pivonello,
C Vitale,
M Amboni,
A De Rosa,
M Moccia,
R Erro, G De Michele,
L Santoro,
A Colao,
P Barone
[show abstract]
[hide abstract]
ABSTRACT: BACKGROUND AND PURPOSE: Cognitive impairment is common in Parkinson's disease (PD), even in the early stages. We aimed to assess the relationship between insulin-like growth factor-1 (IGF-1) and cognitive functions in early, drug-naïve patients with PD. METHODS: Serum IGF-1 was measured in 65 early, drug-naïve patients with PD that underwent a complete neuropsychological battery at baseline and after 2 years. Linear regression analysis was used to evaluate the relationships between neuropsychological scores and IGF-1. Repeated-measures anova was applied to assess changes in neuropsychological variables over time. RESULTS: At baseline, IGF-1 levels were related to phonological fluency. At follow-up, IGF-1 levels were associated with the Rey auditory verbal learning test (RAVLT) - immediate and delayed recall, Frontal Assessment Battery, verbal span and Benton judgement of the line orientation test. Patients with low IGF-1 levels at baseline showed a significantly faster decline of performances than patients with high IGF-1 levels on immediate and delayed recall of the RAVLT and interference task of the Stroop test. CONCLUSIONS: Low serum IGF-1 levels are related to poor performance on executive tasks in early, drug-naïve patients with PD, and may predict poor performance on attention/executive and verbal memory tasks after a 2-year follow-up.
European Journal of Neurology 03/2013; · 3.69 Impact Factor
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Sabina Pappatà,
G Santangelo,
D Aarsland,
C Vicidomini,
K Longo,
K Bronnick,
M Amboni,
R Erro,
C Vitale,
M G Caprio,
M T Pellecchia,
A Brunetti, G De Michele,
M Salvatore,
P Barone
[show abstract]
[hide abstract]
ABSTRACT: To characterize brain metabolic changes associated with mild cognitive impairment (MCI) in drug-naive patients with Parkinson disease (PD) using (18)F-fluorodeoxyglucose (FDG) and PET (FDG-PET).
This cross-sectional study included newly diagnosed patients with PD with MCI in single or multiple domain (PD-MCI; n =12) and without MCI (PD-nMCI; n =12), and healthy controls (n =12). The groups were matched for age. Moreover, the patient groups were matched for motor disability. All subjects underwent a FDG-PET study. Cerebral regional relative metabolic maps were compared in PD-MCI, PD-nMCI, and controls using regions of interest analysis (ROIs) and voxel-based analysis with statistical parametric mapping.
ROIs and voxel-based analyses revealed significant relative hypometabolism in the prefrontal, superior/inferior parietal, and associative occipital cortices as well as in the striatum in patients with PD-MCI relative to controls (p < 0.05) and to a lesser extent in patients with PD-nMCI. In contrast, patients with PD-nMCI did not show significant metabolic changes as compared to controls.
MCI in patients with PD is associated with cortical hypometabolism since the earliest stage, independent of therapy or motor disability. The early involvement of posterior cortical region, a pattern shared by advanced stages of PD-MCI and PD with dementia, could represent an early marker of dementia. The relevance of this pattern in predicting prodromal dementia has to be evaluated in longitudinal studies.
Neurology 09/2011; 77(14):1357-62. · 8.31 Impact Factor
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Parkinsonism & Related Disorders 07/2011; 17(10):771-3. · 3.80 Impact Factor
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C. Colosimo,
N. Vanacore,
V. Bonifati,
G. Fabbrini,
A. Rum, G. De Michele,
M. De Mari,
U. Bonuccelli,
D. J. Nicholl,
G. Meco,
European Study Group on Atypical Parkinsonism (ESGAP) Consortium
Acta Neurologica Scandinavica 06/2008; 103(4):261 - 264. · 2.47 Impact Factor
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G Coppola,
R Lanzillo,
C Florio,
G Orefice,
P Vivo,
S Ascione,
V Schiavone,
A Pagano,
G Vacca, G De Michele,
V Brescia Morra
[show abstract]
[hide abstract]
ABSTRACT: Post-marketing surveillance studies are needed to assess the long-term safety, compliance and clinical efficacy of interferon beta-1a (IFNbeta-1a) therapy in multiple sclerosis (MS) patients. The goals of this study were to (i) assess the safety, compliance and clinical efficacy of long-term intramuscular (i.m.) IFNbeta-1a therapy in a large cohort of patients, and (ii) suggest possible predictors of therapeutic response. A total of 255 patients were included in the study. Mean time on therapy was 31.7 +/- 19.3 months. Within 3 years, 31% of patients discontinued treatment, mainly for disease activity. No significant sustained blood analysis alteration was observed over time, apart from a decrease of cholesterol levels. After 3 years of treatment, mean Expanded Disability Status Scale (EDSS) scores increased by 0.4 points compared with baseline. The mean annual relapse rate was reduced compared with baseline. Patients with < or = 2 relapses in the previous 2 years and with baseline EDSS scores of < or = 2 had a longer estimated time to first relapse and to progression and first relapse, respectively. These results confirm the safety and suggest a sustained effectiveness of i.m. IFNbeta-1a, extending the reported follow-up period to 6.3 years, and hypothesize the presence of possible predictors of clinical outcome.
European Journal of Neurology 10/2006; 13(9):1014-21. · 3.69 Impact Factor
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M Sharma,
J C Mueller,
A Zimprich,
P Lichtner,
A Hofer,
P Leitner,
S Maass,
D Berg,
A Dürr,
V Bonifati, G De Michele,
B Oostra,
A Brice,
N W Wood,
B Muller-Myhsok,
T Gasser
[show abstract]
[hide abstract]
ABSTRACT: Parkinson's disease is a genetically complex disease with mixed mode of inheritance. Recently, a haplotype across the sepiapterin reductase (SPR) gene, which is located in the PARK3 linkage region, was shown to modulate age of onset of Parkinson's disease in sibships from North America.
To make a thorough assessment of the SPR gene region in sporadic Parkinson's disease.
A linkage study in 122 European sibship families with five microsatellite and 17 single nucleotide polymorphism (SNP) markers in and around the SPR gene region, and an association analysis in 340 sporadic cases of Parkinson's disease and 680 control subjects from Germany with 40 SNPs. Linkage was evaluated by non-parametric linkage scores and genotypic or haplotype association was tested by regression analysis, assuming different risk effect models.
Significant LOD scores between 2 and 3 were obtained at the two SPR-flanking markers D2S2110 and D2S1394 and seven SNP markers around the SPR gene. We found the previously reported promoter SNP rs1876487 also significantly associated with age of onset in our sib pair families (p-value 0.02). One strong linkage disequilibrium (LD) block of 45 kb including the entire SPR gene was observed. Within this LD block all 14 inter-correlated SNPs were significantly associated with Parkinson's disease affection status (p-value 0.004).
DNA polymorphisms in a highly intercorrelated LD block, which includes the SPR gene, appear to be associated with both sporadic and familial Parkinson's disease. This confirms a previous study showing that SPR potentially modulates the onset of or risk for Parkinson's disease.
Journal of Medical Genetics 08/2006; 43(7):557-62. · 6.36 Impact Factor
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[show abstract]
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ABSTRACT: The authors performed a multimodal electrophysiologic evaluation in nine patients belonging to four SCA17 (spinocerebellar ataxia type 17) families. Peripheral nerve and visual system were not involved. Brainstem auditory evoked potentials were constantly abnormal with central type lesions. Magnetic motor evoked potentials were abnormal only in the lower limbs, suggesting a length-dependent involvement of the pyramidal tract. Somatosensory evoked potentials were abnormal in almost all our patients, and abnormalities were consistent with a somatosensory pathway involvement along the brainstem.
Neurology 04/2006; 66(6):932-4. · 8.31 Impact Factor
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[show abstract]
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ABSTRACT: Mutations in the parkin gene (PARK2) are the most frequent cause of autosomal recessive early–onset Parkinson disease. We performed a transcranial
magnetic stimulation study in four patients with parkin mutations. Two patients had a prolonged central motor conduction time at both upper and lower limb, one only at the arm and
one only at the leg. The MEP threshold was increased in one patient for the arm and in two for the leg. The MEP amplitude
was reduced in one and central silent period shortened in two. The findings demonstrate corticospinal dysfunction in these
patients and suggest that the extent of central nervous system involvement in parkin disease may be wider that hitherto supposed.
Journal of Neurology 02/2006; 253(3):275-279. · 3.47 Impact Factor
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A Varrone,
M T Pellecchia,
M Amboni,
V Sansone,
E Salvatore,
D Ghezzi,
B Garavaglia,
A Brice,
A Brunetti,
V Bonavita, G De Michele,
M Salvatore,
S Pappatà,
P Barone
[show abstract]
[hide abstract]
ABSTRACT: To investigate whether the presence of parkin gene mutations is associated with different nigrostriatal impairment than other early-onset parkinsonism.
Eighteen consecutive early-onset Parkinson disease (PD) patients (nine parkin and nine nonparkin patients) and six controls were studied with [123I]FP-CIT SPECT.
Parkin patients had longer disease duration (15 +/- 9 vs 6 +/- 2 years, p = 0.008) and higher Unified Parkinson's Disease Rating Scale (UPDRS) motor score (35.8 +/- 13.7 vs 22.8 +/- 7.9, p = 0.025) than nonparkin patients. Caudate and putamen DAT density were reduced by 60% and 79% in parkin and by 43% and 70% in nonparkin patients. Multiple regression analysis showed that the UPDRS and the presence of parkin gene mutations, but not the disease duration, were significantly correlated with the striatal DAT density. Parkin patients showed a more symmetric DAT loss in both caudate and putamen as compared with nonparkin patients.
Parkin-related disease may be associated with a higher degree of nigrostriatal impairment, independently of the clinical severity of the disease, and a more symmetric involvement as compared with non-parkin early-onset disease.
Neurology 01/2005; 63(11):2097-103. · 8.31 Impact Factor
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M Martinez,
A Brice,
J R Vaughan,
A Zimprich,
M M B Breteler,
G Meco,
A Filla,
M J Farrer,
C Bétard,
J Hardy, G De Michele,
V Bonifati,
B Oostra,
T Gasser,
N W Wood,
A Dürr
[show abstract]
[hide abstract]
ABSTRACT: To undertake a full genome-wide screen for Parkinson's disease susceptibility loci.
A genome-wide linkage study was undertaken in 227 affected sibling pairs from 199 pedigrees with Parkinson's disease. The pedigree sample consisted of 188 pedigrees from five European countries, and 11 from the USA. Individuals were genotyped for 391 microsatellite markers at approximately 10 cM intervals throughout the genome. Multipoint model-free affected sibling pair linkage analyses were carried out using the MLS (maximum LOD score) test.
There were six chromosomal regions with maximum MLS peaks of 1 or greater (pointwise p<0.018). Four of these chromosomal regions appear to be newly identified regions, and the highest MLS values were obtained on chromosomes 11q (MLS = 1.60, at 91 cM, D11S4175) and 7p (MLS = 1.51, at 5 cM, D7S531). The remaining two MLS peaks, on 2p11-q12 and 5q23, are consistent with excess sharing in regions reported by other studies. The highest MLS peak was observed on chromosome 2p11-q12 (MLS = 2.04, between markers D2S2216 and D2S160), within a relatively short distance (approximately 17 cM) from the PARK3 region. Although a stronger support of linkage to this region was observed in the late age of onset subgroup of families, these differences were not significant. The peak on 5q23 (MLS = 1.05, at 130 cM, D5S471) coincides with the region identified by three other genome scans. All peak locations fell within a 10 cM distance.
These stratified linkage analyses suggest linkage heterogeneity within the sample across the 2p11-q12 and 5q23 regions, with these two regions contributing independently to Parkinson's disease susceptibility.
Journal of Medical Genetics 12/2004; 41(12):900-7. · 6.36 Impact Factor
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C Casali,
E M Valente,
E Bertini,
G Montagna,
C Criscuolo, G De Michele,
M Villanova,
M Damiano,
A Pierallini,
F Brancati, [......],
G S Grieco,
M Muglia,
M Carella,
B Martini,
A Rossi,
G A Amabile,
G Nappi,
A Filla,
B Dallapiccola,
F M Santorelli
[show abstract]
[hide abstract]
ABSTRACT: A complicated form of recessive hereditary spastic paraplegias (HSPs) with thin corpus callosum (TCC) was first described in Japan, and most of the Japanese families showed linkage to chromosome 15q13-15. A recessive HSP locus (SPG11) has also been mapped to chromosome 15q13-15 in Italian and North American families with and without TCC, and it overlaps the region identified in the Japanese families.
To study clinically and genetically 12 Italian families with HSP and TCC.
The authors investigated 18 affected and 30 healthy individuals from 12 unrelated Italian families with recessive HSP-TCC. Clinical, neurophysiologic, and neuroradiologic studies were undertaken. All patients were negative for SPG7 mutations. Genetic linkage analyses were carried out with polymorphic DNA markers on 15q13-15.
Five families were consistent with linkage, thus defining a 19.8-cM region between markers D15S1007 and D15S978, encompassing the SPG11 interval. In one consanguineous family, linkage could be firmly excluded, confirming genetic heterogeneity. Two families appeared not linked to the region, but this could not be firmly proved because of the small family size. The remaining four families were uninformative for linkage purposes.
HSP-TCC is common in Italy. The phenotype is fairly homogeneous and is associated with impaired cognition. There are at least two loci for HSP-TCC, one of which is on chromosome 15q13-15.
Neurology 02/2004; 62(2):262-8. · 8.31 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: The DJ-1 gene was identified as responsible for early onset autosomal recessive parkinsonism in two families (PARK7). In this study, after excluding mutations in the parkin gene, the authors screened a large series of early onset autosomal recessive parkinsonism families and consanguineous isolated patients of diverse geographic origins for DJ-1 mutations. No mutations were found. This indicates that PARK7 is not a common locus for early onset autosomal recessive parkinsonism, and that one or more new loci remains to be identified.
Neurology 12/2003; 61(10):1429-31. · 8.31 Impact Factor
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N Rawal,
M Periquet,
E Lohmann,
C B Lücking,
H A Teive,
G Ambrosio,
S Raskin,
S Lincoln,
N Hattori,
J Guimaraes, [......],
W Dos Santos Bele,
E Brousolle,
A Destée,
Y Mizuno,
M Farrer,
J-F Deleuze, G De Michele,
Y Agid,
A Dürr,
A Brice
[show abstract]
[hide abstract]
ABSTRACT: The frequency of parkin mutations was evaluated in 30 families of highly diverse geographic origin with early-onset autosomal recessive parkinsonism. Twelve different mutations, six of which were new, were found in 10 families from Europe and Brazil. Patients with parkin mutations had significantly longer disease duration than patients without the mutation but with similar severity of disease, suggesting a slower disease course. Two patients with parkin mutations had atypical clinical presentation at onset, with predominant tremor when standing.
Neurology 05/2003; 60(8):1378-81. · 8.31 Impact Factor
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E M Valente,
F Brancati,
V Caputo,
E A Graham,
M B Davis,
A Ferraris,
M M B Breteler,
T Gasser,
V Bonifati,
A R Bentivoglio, G De Michele,
A Dürr,
P Cortelli,
A Filla,
G Meco,
B A Oostra,
A Brice,
A Albanese,
B Dallapiccola,
N W Wood
[show abstract]
[hide abstract]
ABSTRACT: The Parkin gene is responsible for about 50% of autosomal recessive juvenile parkinsonism (ARJP) and less than 20% of sporadic early onset cases. We recently mapped a novel ARJP locus (PARK6) on chromosome 1p. Linkage to PARK6 was confirmed in 8 families from 4 different European countries. These families share some clinical features with the European Parkin-positive cases, with a wide range of ages at onset and slow progression. However, features typical of ARJP, such as dystonia and sleep benefit, were not observed, making the clinical presentation of late-onset cases indistinguishable from that of idiopathic PD. The determination of the smallest region of homozygosity in one consanguineous family allowed reducing the candidate interval to 9 cM. PARK6 appears to be an important locus for ARJP in Europe.
Neurological Sciences 10/2002; 23 Suppl 2:S117-8. · 1.32 Impact Factor
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E.M. Valente,
F. Brancati,
V. Caputo,
E.A. Graham,
M.B. Davis,
A. Ferraris,
M.M.B. Breteler,
T. Gasser,
V. Bonifati,
A.R. Bentivoglio, G. De Michele,
A. Dürr,
P. Cortelli,
A. Filla,
G. Meco,
B.A. Oostra,
A. Brice,
A. Albanese,
B. Dallapiccola,
N.W. Wood
[show abstract]
[hide abstract]
ABSTRACT: The Parkin gene is responsible for about 50% of autosomal recessive juvenile parkinsonism (ARJP) and less than 20% of sporadic early onset cases. We recently mapped a novel ARJP locus (PARK6) on chromosome 1p. Linkage to PARK6 was confirmed in 8 families from 4 different European countries. These families share some clinical features with the European Parkin-positive cases, with a wide range of ages at onset and slow progression. However, features typical of ARJP, such as dystonia and sleep benefit, were not observed, making the clinical presentation of late-onset cases indistinguishable from that of idiopathic PD. The determination of the smallest region of homozygosity in one consanguineous family allowed reducing the candidate interval to 9 cM. PARK6 appears to be an important locus for ARJP in Europe.
Neurological Sciences 01/2002; 23:s117-s118. · 1.32 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Two brothers presented with late-onset cerebellar ataxia and severe dysphonia. Brain MRI showed vermian and hemispheric cerebellar atrophy. Laringofiberscopy revealed laryngeal abductor paralysis in both patients. Neurophysiologic studies showed a pure motor neuropathy. The combined findings and the molecular analysis suggest a new familial disorder. Inheritance is most likely autosomal recessive, but X-linked transmission is also possible.
Neurology 06/2001; 56(10):1412-4. · 8.31 Impact Factor
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Acta Neurologica Scandinavica 05/2001; 103(4):261-4. · 2.47 Impact Factor
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M Periquet,
C Lücking,
J Vaughan,
V Bonifati,
A Dürr, G De Michele,
M Horstink,
M Farrer,
S N Illarioshkin,
P Pollak,
M Borg,
C Brefel-Courbon,
P Denefle,
G Meco,
T Gasser,
M M Breteler,
N Wood,
Y Agid,
A Brice
[show abstract]
[hide abstract]
ABSTRACT: A wide variety of mutations in the parkin gene, including exon deletions and duplications, as well as point mutations, result in autosomal recessive early-onset parkinsonism. Interestingly, several of these anomalies were found repeatedly in unrelated patients and may therefore result from recurrent, de novo mutational events or from founder effects. In the present study, haplotype analysis, using 10 microsatellite markers covering a 4.7-cM region known to contain the parkin gene, was performed in 48 families, mostly from European countries, with early-onset autosomal recessive parkinsonism. The patients carried 14 distinct mutations in the parkin gene, and each mutation was detected in more than one family. Our results support the hypothesis that exon rearrangements occurred independently, whereas some point mutations, found in families from different geographic origins, may have been transmitted by a common founder.
The American Journal of Human Genetics 04/2001; 68(3):617-26. · 10.60 Impact Factor
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N Vanacore,
V Bonifati,
C Colosimo,
G Fabbrini, G De Michele,
R Marconi,
D Nicholl,
N Locuratolo,
S Romano,
G Talarico,
F Stocchi,
U Bonuccelli,
P Lamberti,
P Vieregge,
G Meco
[show abstract]
[hide abstract]
ABSTRACT: Progressive supranuclear palsy (PSP) is a rare form of parkinsonism. The incidence rates are about 0.3-1.1 cases per 100,000 persons. The only two case-control studies performed up to now show conflictual results as regards education and residence in rural areas. Recently, a cluster of PSP and atypical parkinsonism has been observed in French Antilles. The hypothesis is that a consumption of both tropical fruit and herbal tea may be associated with PSP onset. Some PSP families with a probably autosomal dominant transmission have been described. A high frequency of a tau haplotype (H1/H1) associated with PSP is reported by some authors. The significance of this association is still not clear. We have performed a case-control study on 58 PSP cases, 116 hospital controls and 58 population controls.
Neurological Sciences 03/2001; 22(1):101-3. · 1.32 Impact Factor
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V Bonifati, G De Michele,
C B Lücking,
A Dürr,
E Fabrizio,
G Ambrosio,
N Vanacore,
M De Mari,
R Marconi,
L Capus,
M M Breteler,
T Gasser,
B Oostra,
N Wood,
Y Agid,
A Filla,
G Meco,
A Brice
[show abstract]
[hide abstract]
ABSTRACT: Mutations of the parkin gene on chromosome 6 cause autosomal recessive, early onset parkinsonism. This is the most frequent form of monogenic parkinsonism so far identified. The associated phenotypical spectrum encompasses early onset, levodopa-responsive parkinsonism (average onset in the early 30s in Europe), and it overlaps with dopa-responsive dystonia in cases with the earliest onset, and with clinically typical Parkinson's disease in cases with later onset. Despite clinical features, Lewy bodies are not found at autopsy in brains of patients with parkin mutations. The parkin protein possesses ubiquitin ligase activity, which is abolished by the pathogenic mutations.
Neurological Sciences 03/2001; 22(1):51-2. · 1.32 Impact Factor
